Rat neonates treated systemically with purified gp120, the external envelope protein of the human immunodeficiency virus, exhibited retarded development of complex motor behaviors and widespread dystrophic changes in neuronal morphology. The dystrophic neurons of the cerebral cortex were characterized by reduced dendritic arbor and coarse, thickened dendrites with abnormal spines. Co-administration of peptide T with gp120 prevented or attenuated the retardation in behavioral development. A Sholl analysis of dendritic spread indicated that peptide T prevented the 25% loss observed in cortical neurons from animals treated with gp120 alone. Adult rats given gp120 daily by intracerebroventricular cannula showed impaired acquisition of learning in the Morris water maze test. In saline-injected rats, performance progressively improved over a 15 days of training while animals given gp120 did not improve. PACAP38, a VIP-like neuropeptide isolated from ovine hypothalami, was found to prevent gp120-induced death in murine hippocampal cultures. The potency of PACAP38 was 100-fold greater than VIP in preventing neuronal death associated with gp120.